Three-month outcomes of faricimab loading therapy for wet age-related macular degeneration in Japan

This multicenter study aimed to assess the short-term effectiveness and safety of faricimab in treatment-naïve patients with wet age-related macular degeneration (wAMD) in Japan. We retrospectively reviewed 63 eyes of 61 patients with wAMD, including types 1, 2, and 3 macular neovascularization as well as polypoidal choroidal vasculopathy (PCV). Patients received three consecutive monthly intravitreal injections of faricimab as loading therapy. Over these 3 months, visual acuity improved gradually compared to baseline. Moreover, the central foveal thickness decreased significantly at 1, 2, and 3 months compared to baseline (p < 0.0001). At 3 months after initiation of faricimab therapy, a dry macula (defined as absence of intraretinal or subretinal fluid) was achieved in 82% of the eyes. Complete regression of polypoidal lesions was observed in 52% of eyes with PCV. Subfoveal choroidal thickness also decreased significantly at 1, 2, and 3 months compared to baseline (p < 0.0001). Although retinal pigment epithelium tears developed in two eyes, there were no other ocular or systemic complications observed during the 3 months of loading therapy. In conclusion, loading therapy using faricimab resulted in improved visual acuity and retinal morphology in Japanese patients with wAMD without particular safety issues.

Worldwide, age-related macular degeneration (AMD) is a leading cause of central vision loss in the elderly population [1][2][3] . In the pathologic phase of macular neovascularisation (MNV) in wet AMD (wAMD), angiopoietin-2 (Ang-2) expression increases in the vascular endothelium; this competitively inhibits angiopoietin-1 (Ang-1) from binding tyrosine kinase immunoglobulin-like receptors (Tie 2) on the surface of vascular endothelial cells, thus preventing Ang-1/Tie 2 signalling and resulting in capillary inflammation or pericyte loss 4 . In patients with wAMD, Ang-2 expression is upregulated in the retina and vitreous 5 .
Vascular endothelial growth factor (VEGF) inhibitors are the main treatment option for patients with wAMD; there are several commercially available anti-VEGF agents, including bevacizumab (off-label), ranibizumab, aflibercept, and brolucizumab 6,7 . Intensive research has been conducted on optimal treatment protocols based on these drugs for wAMD 8 . In 2022, the first humanized, bispecific IgG monoclonal antibody, faricimab, which inhibits both VEGF-A and Ang-2, was approved after two phase 3 trials (TENAYA and LUCERNE). It demonstrated the visual benefits of treatment with faricimab given at up to 16-week intervals in patients with wAMD 9 . This study aimed to evaluate the safety and efficacy of faricimab treatment for patients with wAMD in real-world settings.

Discussion
This Japanese multicentre study demonstrated visual and anatomical improvement as well as the general safety of loading therapy with faricimab in untreated eyes with wAMD. BCVA improved 2 months after the first faricimab treatment, which further improved at 3 months. The loading therapy of faricimab gradually induced these improvements in patients with wAMD. In comparison, we reported that the short-term BCVA significantly improved 1 month after the first brolucizumab injection in patients with wAMD, except for those with PCV 10 . Matsumoto et al. reported similar results in patients with type 1 MNV 11 . However, Fukuda et al. reported that visual function significantly recovered 3 months after treatment with aflibercept in eyes with PCV 12 , but no significant recovery was achieved at 3 months by treatment with brolucizumab. Moreover, 35%, 69%, and 82% of patient eyes in our study attained a dry macula at 1, 2, and 3 months, respectively, and polypoidal lesions completely disappeared in 50% of the patients with PCV. We previously reported that dry macular rates 3 months after brolucizumab treatment were 91%, 88%, and 100% for type 1 and/or type 2  www.nature.com/scientificreports/  www.nature.com/scientificreports/ MNV, PCV, and type 3 MNV, respectively 10 . Another study reported dry macula rates of 47.2%, 86.1%, and 94.4% at 1, 2, and 3 months, respectively, after treatment with brolucizumab 11 in type 1 MNV. Among patients with PCV treated with aflibercept, the SRF-free rates were 44.7%, 76.3%, and 84.2% at 1, 2, and 3 months after aflibercept treatment, respectively, while the corresponding values after brolucizumab treatment were 64.3%, 85.7%, and 100% 12 . Overall, the improvement in visual function and retinal anatomy after treatment with faricimab during loading therapy was comparable to that after treatment with aflibercept. In our cohort, faricimab allowed complete regression of polypoidal lesions in 50% of patients with PCV. In our previous study, the rate of complete regression of polypoidal lesions in eyes treated with aflibercept was 47.8% 13 , which is consistent with other reports 14,15 . In eyes treated with brolucizumab, the regression rate has been reported to be 73.9-78.9% 12,16 . Thus, faricimab and aflibercept have similar effects on the regression of polypoidal lesions. Furthermore, the loading treatment significantly reduced the SCT in the affected eyes. VEGF is secreted from the basement membrane of the RPE to maintain choroidal homeostasis 17 . Ang-1-Tie 2 receptors are expressed in the choroid 5 , where they maintain the stability of choroidal vessels 18 . As faricimab affects these receptors, it could also affect choroidal vessels. Accordingly, there was a decrease in SCT at 1, 2, and 3 months after initiation of faricimab treatment (by 93%, 90%, and 88%, respectively). In our previous study, the SCT decreased by 91.3%, 89.8%, and 86.5% at 1, 2, and 3 months, respectively, after treatment with aflibercept in PCV cases 19 . Related results regarding the effects of aflibercept 20,21 on SCT have been reported. Moreover, in our previous study, SCT in eyes with wAMD decreased by 90.6%, 86.6%, and 84.7% at 1, 2, and 3 months, respectively, after treatment with brolucizumab 22 . In other studies, SCT in eyes with type 1 MNV or PCV decreased by 83.3-89.4%, 82.5-86.0%, and 84.1-84.4% at 1, 2, and 3 months, respectively, after treatment with brolucizumab 11,12 . Faricimab might have a slightly lower impact on the choroid than brolucizumab.
There were two cases of RPE tears: one developed 1 month after the first faricimab treatment in an eye with type 1 and type 2 MNV, while the other developed at 3 months in an eye with PCV. By the end of the loading therapy, the bilateral visual acuity was maintained. In a study conducted by TENAYA and LUCERNE, RPE tears after treatment with faricimab developed in five eyes (1.3%) and three eyes (0.9%), respectively 9 . This trend requires careful monitoring in patients with a large PED, in which active type 1 MNV spreads through sub-RPE fluid 23 .
In the 3 months after initiation of faricimab treatment, no cases with ocular inflammation were observed, even though in the previous phase 3 trials (TENAYA and LUCERNE), 1.3% and 1.5% ocular adverse events were reported in each, respectively, including 0.3% and 0.6% vitritis, 0.5% and 0.6% iritis, and 0.5% and 0.6%   www.nature.com/scientificreports/ uveitis, respectively. Ang-2 may be essential for constructing normal vasculature in response to physiological events 24 ; however, reducing Ang-2 can reduce inflammation, as was shown in a mouse model of myocardial infarction 25 . It is possible that the anti-inflammatory effects of Ang-2 inhibition contributed to the low rate of ocular inflammation. The limitations of this study include its retrospective nature and short follow-up period. Thus, further studies are required to verify the long-term efficacy and safety of faricimab in patients with wAMD.
In conclusion, a loading therapy of faricimab effectively improved visual acuity and retinal morphology in eyes with wAMD. Ophthalmologists should carefully monitor safety during follow-up.

Methods
This study included 63 untreated eyes of 61 patients with neovascular AMD, who visited the Fukushima Medical University Hospital; Kyorin University Hospital; Nihon University Hospital; University of the Ryukyus Hospital; and Tokyo Women's Medical University Hospital (Japan AMD Research Consortium: JARC) between June 2022 and August 2022. The study protocol was approved by the Institutional Review Board of Fukushima University, Kyorin University Hospital, Nihon University Hospital, Ryukyus Hospital and Tokyo Women's Medical University Hospital as a retrospective study. All study protocols adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all the patients included in this study. We included untreated patients with wAMD aged ≥ 45 years. We excluded patients with myopia of > − 6 dioptres, a history of uveitis, or a history of vitrectomy. One patient (1 eye) did not return for personal reasons. Accordingly, we included 62 eyes from 60 patients who received faricimab at 1-month intervals for 3 consecutive months, with assessments at baseline and then after 1 and 2 months. The outcomes included visual acuity, fluid resolution rate, CFT, SCT, changes in PED, and polypoidal lesion regression rate in patients with PCV after 3 months. Fluorescein angiography (FA) and indocyanine green angiography (ICGA) were performed using a confocal scanning laser ophthalmoscope (Spectralis HRA + OCT; Heidelberg Engineering) to determine the subtypes of neovascular AMD, including type 1 MNV, type 2 MNV 26 , PCV 27 , and type 3 MNV 26 . PCV was diagnosed based on the presence of polypoidal lesions on ICGA 27 . The diagnosis criteria for type 3 MNV were retinal-retinal anastomosis on early-phase FA or ICGA and a hot spot on late-phase ICGA 28 . We determined the BCVA using the early treatment diabetic retinopathy study (ETDRS) visual acuity chart at Nihon University as well as the Landolt C chart at the other four institutions. BCVA was converted to the logarithm of the minimal angle of resolution (logMAR) units for outcome analyses. On the OCT images, the macula was considered dry if the subretinal and intraretinal fluids were completely resolved. CFT was measured from the superior border of the RPE to the border of the inner retinal layer at the foveal centre. Additionally, SCT was measured as the vertical distance between the hyperreflective line corresponding to Bruch's membrane under the RPE and the inner scleral boundary at the foveal  PED was defined as one or more detached areas, the same size as the optic disc, in the macula on FA; its height was also recorded for comparison with previous measurements. The height of PED from the inner layer of Bruch's membrane to the top of the RPE was measured using OCT. Changes in polypoidal lesions were recorded as complete regression, partial regression, or increase relative to baseline levels as measured using ICGA. Exclusion criteria were massive submacular haemorrhages extending beyond the equator.
Statistical analysis. Data are presented as the mean ± standard deviation (SD). The Wilcoxon signed-rank test was used to assess changes in visual acuity. One-way analysis of variance was used to compare CRT and SCT before and after treatment. Statistical significance was set at p < 0.05. GraphPad Prism version 9 (GraphPad Software, LLC) was used for the statistical analyses.

Data availability
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. www.nature.com/scientificreports/